7 8 9 10-tetrahydro-6h-azepino, 6 7 8 9-tetrahydro-pyrido and 2 3-dihydro-2h-pyrrolo[2 1-b]-quinazolinone derivates

ABSTRACT

The invention relates to novel 7,8,9,10-tetrahydro-6H-azepino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro-2H-pyrrolo[2, 1-b]-quinazolinone derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.

The present invention relates to novel 7,8,9,10-tetrahydro-6H-azepino,6,7,8,9-tetrahydro-pyrido and2,3-dihydro-2H-pyrrolo[2,1-b]-quinazolinone derivatives of the generalformula I and their use as pharmaceuticals. The invention also concernsrelated aspects including processes for the preparation of thecompounds, pharmaceutical compositions containing one or more compoundsof formula I, and especially their use as orexin receptor antagonists.

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and theorexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al., Cell, 1998,92, 573-585). Orexins are found to stimulate food consumption in ratssuggesting a physiological role for these peptides as mediators in thecentral feedback mechanism that regulates feeding behavior (Sakurai T.et al., Cell, 1998, 92, 573-585). On the other hand, it was alsoproposed that orexins regulate states of sleep and wakefulness openingpotentially novel therapeutic approaches for narcoleptic patients(Chemelli R. M. et al., Cell, 1999, 98, 437-451). Two orexin receptorshave been cloned and characterized in mammals. They belong to thesuperfamily of G-protein coupled receptor (Sakurai T. et al., Cell,1998, 92, 573-585): the orexin-1 receptor (OX₁) is selective for OX-Aand the orexin-2 receptor (OX₂) is capable to bind OX-A as well as OX-B.

Orexin receptors are found in the mammalian host and may be responsiblefor many biological functions such as pathologies including, but notlimited to, depression; anxiety; addictions; obsessive compulsivedisorder; affective neurosis; depressive neurosis; anxiety neurosis;dysthymic disorder; behaviour disorder; mood disorder; sexualdysfunction; psychosexual dysfunction; sex disorder; schizophrenia;manic depression; delerium; dementia; severe mental retardation anddyskinesias such as Huntington's disease and Tourette syndrome; feedingdisorders such as anorexia, bulimia, cachexia and obesity; diabetes;appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson'sdisease; Cushing's syndrome/disease; basophil adenoma; prolactinoma;hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma;hypothalamic diseases; inflammatory bowel disease; gastric diskinesia;gastric ulcus; Froehlich's syndrome; adrenohypophysis disease;hypophysis disease; pituitary growth hormone; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; disturbed biological andcircadian rhythms; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome; heatand lung diseases, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischaemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; migraine;hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such ashyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypicalfacial pain; neuropathic pain; back pain; complex regional pain syndromeI and II; arthritic pain; sports injury pain; pain related to infectione.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; conditions associated with visceral pain such as irritablebowel syndrome, migraine and angina; urinary bladder incontinence e.g.urge incontinence; tolerance to narcotics or withdrawal from narcotics;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; and neurodegerative disorders including nosological entitiessuch as disinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration epilepsy; seizure disorders and otherdiseases related to orexin.

The present invention provides 7,8,9,10-tetrahydro-6H-azepino,6,7,8,9-tetrahydro-pyrido and2,3-dihydro-2H-pyrrolo[2,1-b]-quinazolinone derivatives which arenon-peptide antagonists of human orexin receptors. In particular, thesecompounds are of potential use in the treatment of obesity and/or sleepdisorders.

International Patent Applications WO099/09024, WO099/58533, WO00/47577,WO00/47580, disclose phenyl urea derivatives and WO00/47576, disclosesquinolinyl cinnamide derivatives as orexin antagonists.

Furthermore, WO 0196302 has been published wherein piperidinederivatives as OX₁ and OX₂ antagonists are disclosed and WO 0185693 hasbeen published wherein N-acyltetrahydroisoquinoline derivatives asselective OX₂ antagonists are disclosed. In addition, WO 0244172describes morpholine derivatives as antagonists of orexin receptors.

The novel compounds of the present invention belong to an entirelydifferent class of low molecular weight compounds as compared to allprior art orexin receptor antagonists so far published.

The present invention relates to novel 7,8,9,10-tetrahydro-6H-azepino,6,7,8,9-tetrahydro-pyrido and2,3-dihydro-2H-pyrrolo[2,1-b]-quinazolinone derivatives of the generalformula (I).

wherein:

-   -   X is O or S;    -   n is the integer 1, 2, or 3;    -   m is the integer 0, 1, 2, 3;    -   R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,        hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy,        lower alkenyloxy, trifluoromethyl, trifluoromethoxy,        cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy,        heterocyclyl-lower alkyloxy, R⁸CO—, NR⁹R¹⁰CO—, R⁹R¹⁰N—, R⁸OOC—,        R⁸SO₂NH—,    -   R¹¹—CO—NH or R² and R³ together or R¹ and R² together or R³ and        R⁴ together may form with the phenyl ring a five, six or        seven-membered ring containing one or two oxygen atoms which are        separated by at least one carbon atom;    -   R⁵ represents aryl, aralkyl, lower alkyl, cycloalkyl,        cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower        alkyl;    -   R⁶ represents hydrogen, lower alkyl, trifluoromethyl,        —(CH₂)_(m)—OH, —(CH₂)_(m)—O-lower alkyl, —(CH₂)_(m)—CO₂H,        —(CH₂)_(m)—CO₂-lower alkyl, —(CH₂)_(m)CONH₂, or        —(CH₂)_(m)—CONH-lower alkyl, or —(CH₂)_(m)—CON-(lower alkyl)₂,        or —(CH₂)_(m)—N-(lower alkyl)₂;    -   R⁷ represents aryl, aralkyl, lower alkyl, lower alkenyl,        cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl or        heterocyclyl-lower alkyl;    -   R⁸ represents lower alkyl, aryl, aralkyl, heterocyclyl or        heterocyclyl-lower alkyl;    -   R⁹ and R¹⁰ independently represent hydrogen, alkyl, cycloalkyl,        cycloalkyl-lower alkyl, aryl, aralkyl, heterocyclyl or        heterocyclyl-lower alkyl;    -   R¹¹ represents alkyl, aryl, cycloalkyl, heterocyclyl, R⁹R¹⁰N— or        R⁸O—.

The compounds of formula I can contain one or more asymmetric centresand can be present in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates, mixture of diastereoisomeric racemates, or meso forms andpharmaceutically acceptable salts thereof.

In the present description the term “lower alkyl”, alone or incombination, signifies a straight-chain or branched-chain alkyl groupwith 1 to 8 carbon atoms, preferably a straight or branched-chain alkylgroup with 1-5 carbon atoms. Examples of straight-chain and branchedC₁-C₈ alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, isobutyl, tert-butyl, the isomericpentyls, the isomeric hexyls, the isomeric heptyls and the isomericoctyls, preferably methyl, ethyl, n-proplyl, isopropyl, n-butyl,2-butyl, tert-butyl and n-pentyl.

The term “lower alkenyl”, alone or in combination, signifies astraight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms,preferably allyl and vinyl.

The term “lower alkoxy”, alone or in combination, signifies a group ofthe formula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy.

Lower alkenyloxy groups are preferably vinyloxy and allyloxy.

The term “cycloalkyl”, alone or in combination, signifies a cycloalkylring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to6 carbon atoms. Examples of C₃-C₈ cycloalkyl are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,preferably cyclopropyl, cyclohexyl or lower alkyl substituted cycloalkylwhich may preferably be substituted with lower alkyl such asmethyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl,methyl-cyclopentyl, methyl-cyclohexyl, dimethyl-cyclohexyl,

The term “aryl”, alone or in combination, signifies a phenyl or naphthylgroup which optionally carries one or more substituents, preferably oneor two substituents, each independently selected from cyano, halogen,hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy,nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy, alkoxycarbonyland the like, such as phenyl, p-tolyl, 4-methoxyphenyl,4-tert-butoxyphenyl, 4-fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl,1-naphthyl and 2-naphthyl. Preferred are carboxyphenyl, loweralkoxy-phenyl, hydroxyphenyl and particularly phenyl.

The term “aralkyl”, alone or in combination, signifies an alkyl orcycloalkyl group as previously defined in which one hydrogen atom hasbeen replaced by an aryl group as previously defined. Preferred arebenzyl and benzyl substituted in the phenyl ring with hydroxy, loweralkyl, lower alkoxy or halogen preferably fluorine. Particularlypreferred is benzyl.

For the term “heterocyclyl” and “heterocyclyl-lower alkyl”, theheterocyclyl group is preferably a 5- to 10-membered monocyclic orbicyclic ring, which may be saturated, partially unsaturated or aromaticcontaining for example 1, 2 or 3 heteroatoms selected from oxygen,nitrogen and sulphur which may be the same or different. Example of suchheterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl,isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl,pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl,oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl,pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. Theheterocyclyl group may have up to 5, preferably 1, 2 or 3 optionalsubstituents. Examples of suitable substituents include halogen, loweralkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and loweralkyloxy-carbonyls.

The term “halogen” signifies fluorine, chlorine, bromine or iodine andpreferably chlorine and fluorine and particularly fluorine.

The term “carboxy”, alone or in combination, signifies a —COOH group.Preferred compounds are compounds of the general formula I wherein n isthe integer 1 or 2, m is the integer 0, 1 or 2, R¹, R², R³, R⁴, R⁵, R⁶and R⁷ have the meaning given in the formula I above and X representsoxygen.

Examples of preferred compounds are:

-   1-(9-Oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-Biphenyl-2-yl-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-Naphthalen-1-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethyl-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl-3-(2-n-propyl-phenyl)-urea;-   1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea;-   1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   3-Biphenyl-2-yl-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethyl-phenyl)-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(6-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   3-Biphenyl-2-yl-1-(7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-butyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;-   1-Butyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-n-propylpphenyl)-urea;-   1-Benzyl-3-biphenyl-2-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;-   1-Benzyl-3-(2-ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;-   1-Benzyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3yl)-3-(2-n-propyl-phenyl)-urea;-   3-Biphenyl-2-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-(2-Ethyl-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethoxy-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   3-Naphthalen-1-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2ethoxy-phenyl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(3-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-(2-Ethoxy-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethyl-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-(2-Ethyl-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   3-(2-Ethoxy-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-naphthalen-1-yl-1-(1-phenyl-ethyl)-urea.

Especially preferred compounds are compounds of the general formula Iwherein n is the integer 1 or 2, m is the integer 0, R⁵ representsmethyl, R⁶ represents phenyl, R¹, R², R³, R⁴, and R⁷ have the meaninggiven in the formula I above and X represents oxygen.

Examples of especially preferred compounds are:

-   3-Biphenyl-2-yl-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethyl-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   3-Biphenyl-2-yl-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   3-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(6-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   3-Biphenyl-2-yl-1-(8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;-   1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(3-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-(2-Ethyl-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethoxy-phenyl)-1-(1-phenyl-ethyl)-urea;-   1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-(2-Ethyl-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   3-(2-Ethoxy-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;-   1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-Biphenyl-2-yl-1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea;-   1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   1-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;-   1-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;-   3-(2-Ethyl-phenyl)-1-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea;-   3-Biphenyl-1-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea.

Examples of physiologically usable or pharmaceutically acceptable saltsof the compounds of formula (I) are salts with physiologicallycompatible mineral acids such as hydrochloric acid, sulphuric orphosphoric acid; or with organic acids such as methanesulphonic acid,acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleicacid, tartaric acid, succinic acid or salicylic acid. The compounds offormula (I) with free acidic groups can also form salts withphysiologically compatible bases. Examples of such salts are alkalimetal, alkali earth metal, ammonium and alkylammonium salts such as Na,K, Ca or tetraalkylammonium salt. The compounds of formula (I) can alsobe present in the form of a zwitterion.

The compounds of formula (I) can contain several asymmetric centres andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diasteroisomericracemates or mixtures of diastereoisomeric racemates and the meso-forms.

Preferred compounds as described above have IC₅₀ values below 500 nM;especially preferred compounds have IC₅₀ values below 100 nM which havebeen determinated with the FLIPR (Fluorometric Imaging Plates Reader)method described in the beginning of the experimental section.

The compounds of the general formula (I) and their pharmaceuticallyusable salts can be used for the treatment of diseases or disorderswhere an antagonist of a human orexin receptor is required such asobesity, diabetes, prolactinoma, cardiovascular disorders, cancer, pain,narcolepsy, sleep disorders like insomnia, sleep apnea, parasomnia,depression, anxiety, addictions, schizophrenia, neurodegenerativedisorders and dementia.

The compounds of formula (I) and their pharmaceutically usable salts areparticularly useful for the treatment of obesity and sleep disorders.

The compounds of formula I may also be used in combination with one ormore other therapeutically useful substances e.g. with other orexinreceptor antagonists, with lipid lowerer agents, with anorectic agents,with sleep inducing agents, with antidepressants or with other drugsbeneficial for the prevention of treatment of obesity or sleepdisorders.

The compounds of formula (I) and their pharmaceutically usable salts canbe used as medicament (e.g. in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered in enteral or oralform (e.g. in the form of tablets, coated tablets, dragees, hard andsoft gelatine capsules, solutions, emulsions or suspensions), nasally(e.g. in the form of nasal sprays) or rectally (e.g. in the form ofsuppositories). However, the administration can also be effectedparentally, such as intramuscularly or intravenously (e.g. in the formof injection solutions).

The compounds of formula (I) and their pharmaceutically usable salts canbe processed with pharmaceutically inert, inorganic or organic adjuvantsfor the production of tablets, coated tablets, dragees, and hardgelatine capsules. Lactose, corn starch or derivatives thereof, talc,stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragees, and hard gelatine capsules.

Suitable adjuvants for soft gelatine capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Morever, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The invention also relates to processes for the preparation of compoundsof Formula I.

The compounds of general formula (I) of the present invention areprepared according to the general sequence of reactions outlined in theschemes below, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ are as defined informula (I) above. As the case may be any compound obtained with one ormore optically active carbon atom may be resolved into pure enantiomersor diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates and the meso-forms in a manner known per se.

The compounds obtained may also be converted into a pharmaceuticallyacceptable salt thereof in a manner known per se.

The compounds of general formula (I) may be prepared from thecorresponding 2-amino benzoic acid derivatives with the desired lactamby treatment with POCl₃ (Karimov A. et al Chemistry of Natural Compounds1982, 18, 4, 466-472; Bhardwaj V. et al Indian Journal of HeterocyclicChemistry 1999, 8, 173-176). Subsequent radical bromination (Kamal A. etal J. Org. Chem. 2001, 66, 997-1001) followed by substitution with thecorresponding primary amine gave the secondary amine intermediate whichis then converted to the desired urea or thiourea compound by reactionwith commercially available or synthetized isocyanate or isothiocyanate(Scheme 1) (March J. Advanced Organic Chemistry-Reactions, Mechanismsand Structure 1992, page 418, 4^(th) edition, John Wiley & Sons)

2-Amino benzoic acid derivatives wherein R¹ and R⁴ are hydrogen andwhich are not commercially available might be prepared from benzoic acidderivatives using standard procedures (Giencke A. et al Liebigs Ann.Chem. 1990, 569-579; Follope M.-P. et al Eur. J. med. Chem. 1992, 27,291-295) as described in Scheme 2.

Furthermore, 2-amino benzoic acid derivatives may also be prepared fromaniline derivatives by reaction with chloral hydrate in the presence ofhydroxylamine hydrochloride followed by acidic treatment yielding theisatin intermediate. This was converted to the corresponding anthranilicacid derivative by reaction with hydrogen peroxide under basicconditions (Scheme 3) (Neal Bramson H. et al J. Med. Chem. 2001, 44,4339-4358; Deady L. W. et al J. Med. Chem. 1997, 40, 2040-2046; RowleyM. et al J. Med. Chem. 1993, 36, 3386-3396; Hughes P. et al J.Heterocyclic Chem. 1990, 27, 2151-2163).

Experimental SectionI. BiologyDetermination of OX₁ and OX₂ Receptor Antagonistic Activities

The OX₁ and OX₂ receptor antagonistic activity of the compounds offormula (I) was determined in accordance with the following experimentalmethod.

Experimental Method

Intracellular Calcium Measurements

Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptoror the human orexin-2 receptor, were grown in culture medium (Ham F-12with L-Glutamine) containing 300 μg/ml G418, 100 U/ml penicillin, 100μg/ml streptomycin and 10% inactivated foetal calf serum (FCS).

The cells were seeded at 80'000 cells/well into 96-well black clearbottom sterile plates (Costar) which had been precoated with 1% gelatinein Hanks' Balanced Salt Solution (HBSS). All reagents were from GibcoBRL.

The seeded plates were incubated overnight at 37° C. in 5% CO₂.

Human orexin-A as an agonist was prepared as 1 mM stock solution inmethanol:water (1:1), diluted in HBSS containing 0.1% bovine serumalbumin (BSA) and 2 mM HEPES for use in the assay at a finalconcentration of 10 nM.

Antagonists were prepared as 10 mM stock solution in DMSO, then dilutedin 96-well plates, first in DMSO, then in HBSS containing 0.1% bovineserum albumin (BSA) and 2 mM HEPES.

On the day of the assay, 100 μl of loading medium (HBSS containing 1%FCS, 2 mM HEPES, 5 mM probenecid (Sigma) and 3 μM of the fluorescentcalcium indicator fluo-3 AM (1 mM stock solution in DMSO with 10%pluronic acid) (Molecular Probes) was added to each well.

The 96-well plates were incubated for 60 min at 37° C. in 5% CO₂. Theloading solution was then aspirated and cells were washed 3 times with200 μl HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 μlof that same buffer was left in each well. Within the FluorescentImaging Plate Reader (FLIPR, Molecular Devices), antagonists were addedto the plate in a volume of 50 μl, incubated for 20 min and finally 100μl of TABLE 1 IC₅₀ (nM) OX₁ OX₂ Example 3 115 79 Example 7 2400 27Example 28 153 17 Example 30 261 16 Example 33 127 18 Example 40 37 14Example 41 52 14 Example 44 67 27 Example 49 12 16 Example 50 14 18Example 51 28 21agonist was added. Fluorescence was measured for each well at 1 secondintervals, and the height of each fluorescence peak was compared to theheight of the fluorescence peak induced by 10 nM orexin-A with buffer inplace of antagonist. For each antagonist, IC₅₀ value (the concentrationof compound needed to inhibit 50% of the agonistic response) wasdetermined. The IC₅₀ values of selected compounds are given in Table 1.II. Chemistry

The following examples illustrate the preparation of pharmacologicallyactive compounds of the invention but do not at all limit the scopethereof. All temperatures are stated in ° C.

All hydrochloride salts were prepared by dissolving the free-base indichloromethane and treating with an excess of ethereal HCl (2M).

A. Abbreviations

-   AIBN 2,2′-azobisisobutyronitrile-   BSA Bovine serum albumine-   CHO Chinese hamster ovary-   DMF Dimethylformamide-   eq equivalent-   ES Electron spray-   EtOH Ethanol-   FC Flash chromatography-   FCS Foetal calf serum-   FLIPR Fluorescent imaging plate reader-   HBSS Hank's balanced salt solution-   HEPES 4-(2-Hydroxyethyl)-piperazine-1-ethanesulfonic acid-   m multiplet (NMR)-   MeCN Acetonitrile-   MeOH Methanol-   MS Mass spectroscopy-   NBS N-bromosuccinimide-   NMR Nuclear magnetic resonance-   LC Liquid chromatography-   q quartet (NMR)-   R_(t) retention time-   rt Room temperature-   s singlet (NMR)-   t triplet (NMR)-   TEA Triethylamine-   THF Tetrahydroftiran

B. 2,3-Dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one derivatives

General Procedure:

To a mixture of a 2-aminobenzoic acid derivative (1 g), 2-pyrrolidone(1.5 eq), was added carefully POCl₃ (2.5 mL). The resulting mixture wasstirred at 100° C. for 1 h under nitrogen. After cooling, the reactionmixture was poured into ice-water, basified with sat. NaHCO₃, extractedwith CH₂Cl₂ (3×100 mL). The combined extracts were dried (anhydrousMgSO₄), filtered and concentrated to give a crude brown-yellow viscousoil. FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as a solid.

1) 2,3-Dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as a yellow solid(0.97 g, 71%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.92 min. m/z=187 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.2 (2H, m), 3.2 (2H, m), 4.2 (2H, m), 7.4(1H, t), 7.7 (1H, m), 8.3 (1H, d).

2) 5-Fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as brown solid (0.92g, 70%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.21 min. m/z=205 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.25 (2H, t), 4.2 (2H, t), 7.4(2H, m), 8.1 (1H, d).

3) 6-Fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as yellow crystals(0.79 g, 60%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.16 min. m/z=206 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.2 (2H, t), 4.2 (2H, t), 7.15(1H, m), 7.4 (1H, dd), 8.3 (1H, t).

4) 7-Fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as yellow crystals(0.97 g, 74%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.1 min. m/z=206 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.2 (2H, t), 4.2 (2H, t), 7.4(1H, m), 7.7 (1H, m), 7.95 (1H, dd).

5) 6,7-Difluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as orange crystals(0.86 g, 67%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.39 min. m/z=224 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, t), 3.2 (2H, t), 4.2 (2H, t), 7.4(1H, m), 8.00 (1H, m).

6) 6-Chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as yellow crystals(1.11 g, 86%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.55 min. m/z=222 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.2 (2H, t), 4.2 (2H, t), 7.4(1H, d),7.6 (1H, s), 8.2 (1H, d).

7) 7-Chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as a yellow solid(1.14 g, 89%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.52 min. m/z=222 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.2 (2H, t), 4.2 (2H, t), 7.6(2H, q), 8.3 (1H, s).

8) 8-Chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as a yellow solid(0.97 g, 75%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.30 min. m/z=222 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.2 (2H, t), 4.2 (2H, t), 7.4(1H, m), 7.6 (2H, m).

9) 8-Trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

A mixture of 2-amino-6-trifluoromethyl-benzoic acid (0.97 g),2-methoxypyrroline (0.703 g, 1.5 eq) in dry toluene (12 mL) was stirredat reflux for 3 h. The orange solution was then evaporated to dryness togive a crude orange solid

FC (CH₂Cl₂/MeOH: 9/1) afforded the title compound as a yellow powder(0.89 g, 74%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.90 min. m/z=255 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.3 (2H, q), 3.2 (2H, t), 4.25 (2H, t), 7.75(1H, t), 7.85 (2H, d).

C. 3-Bromo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one derivatives

General Procedure

A mixture of a 2,3-Dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one derivative(1 eq), NBS (1 eq), AIBN (0.085 eq) in dry CHCl₃ (20 mL/ g) was stirredat reflux for 20 h under nitrogen. After cooling, the mixture wasconcentrated under reduced pressure, the resulting crude solid waspurified by FC (AcOEt/heptane: 7/3) to give the title compound.

1) 3-Bromo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/ heptane: 7/3) afforded the title compound as brown crystals(40%).

LC-MS (MeCN/H₂O:1/1): R_(t)=3.49 min. m/z=266 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.55-2.8 (2H, m), 4.1-4.5 (2H, m), 5.3 (1H,d), 7.5 (1H, m), 7.7 (1H, m), 8.3 (1H, d).

2) 3-Bromo-5-fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a n orange solid(35%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.77 min. m/z=285 (M+2).

¹H-NMR (300 MHz; CDCl₃) δ 2.6-2.85 (2H, m), 4.2-4.45 (2H, m), 5.35 (1H,d), 7.5 (2H, m), 8.1 (1H, d).

3) 3-Bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a n orange solid(52%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.70 min. m/z=284 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.55-2.8 (2H, m), 4.1-4.5 (2H, m), 5.3 (1H,d), 7.2 (1H, m), 7.5 (1H, m), 8.3 (1H, m).

4) 3-Bromo-7-fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a reddish solid(53%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.65 min. m/z=284 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.6-2.85 (2H, m), 4.2-4.5 (2H, m), 5.3 (1H,d), 7.5 (1H, m), 7.7 (1H, m), 7.95 (1H, m).

5) 3-Bromo-6,7-difluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a red solid(69%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.01 min. m/z=302 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.55-2.8 (2H, m), 4.05-4.5 (2H, m), 5.3 (1H,d), 7.5 (1H, m), 8.1 (1H, m).

6) 3-Bromo-6-chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a reddish solid(42%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.16 min. m/z=300 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.6-2.85 (2H, m), 4.1-4.5 (2H, m), 5.3 (1H,d), 7.5 (1H, dd), 7.7 (1H, s), 8.3 (1H, d).

7) 3-Bromo-7-chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a pink solid(49%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.12 min. m/z=300 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.55-2.85 (2H, m), 4.1-4.5 (2H, m), 5.3 (1H,d), 7.7 (2H, s), 8.3 (1H, s).

8) 3-Bromo-8-chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a violet powder(38%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.56 min. m/z=300 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.55-2.85 (2H, m), 4.1-4.5 (2H, m), 5.3 (1H,d), 7.5 (1H, dd), 7.8 (2H, m).

9)3-Bromo-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a red solid(36%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.47 min. m/z=334 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.55-2.85 (2H, m), 4.2-4.5 (2H, m), 5.3 (1H,d), 7.8 (1H, t), 7.9 (2H, m).

C. 3-(1-Phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-onederivatives

General Procedure

A mixture of a 3-bromo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-onederivative (0.56 g, 2.11 mmol), (D,L)-α-methylbenzylamine (1 eq), TEA(1.5 eq) in dry EtOH (10 mL), was stirred at reflux for 20 h undernitrogen. After cooling, the reaction mixture was combined withCH₂Cl₂/water and the aqueous phase was extracted twice with CH₂Cl₂. Thecombined extracts were dried (anhydrous MgSO₄), filtered andconcentrated to give a dark green residue as mixture ofdiastereoisomers.

1) 3-(1-Phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark greensolid (69%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.00 min. m/z=306 (M+1).

2)6-Fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark oil (56%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.18 min. m/z=324 (M+1).

3)7-Fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark brown oil(62%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.06 min. m/z=324 (M+1).

4)6,7-Difluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark green oil(42%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.31 min. m/z=342 (M+1).

5)6-Chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark green oil(50%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.40 min. m/z=340 (M+1).

6)7-Chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark brown oil(54%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.34 min. m/z=340 (M+1).

7)8-Chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

FC (AcOEt/heptane: 7/3) afforded the title compound as a dark brown oil(71%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.21 min. m/z=340 (M+1).

8)3-((S)-1-Phenyl-ethylamino)-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

Reaction with the (S)-α-methylbenzylamine

FC (AcOEt) afforded the title compound as a dark brown oil (68%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.63 min. m/z=374 (M+1).

9)5-Fluoro-3-((S)-1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

Reaction with the (S)-α-methylbenzylamine

FC (AcOEt) afforded the title compound as a dark green oil (58%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.36 min. m/z=324 (M+1).

D. 6,7,8,9-Tetrahydro-pyrido[2,1-b]quinazolin-11-one derivatives

General Procedure

To a suspension of 2-aminobenzoic acid derivative (1 eq) in dry CHCl₃(20 mL/g), was added slowly POCl₃ (1.3 eq) accompanied by stirring for15 min at rt under nitrogen. Then δ-valerolactam (1.1 eq) was addedportionwise over a period of 10 min, the reaction mixture was stirred atreflux under nitrogen for 3 h. Aqueous HCl 5% was added to the reactionmixture, the aqueous phase was separated (this operation was repeatedthree times). The combined aqueous extracts were clarified by addingactive charcoal and filtered through celite. The resulting pale yellowsolution was basified with concentrated aqueous ammoniac and extractedwith CH₂Cl₂ (three times). The combined organic extracts were washedwith water, dried (anhydrous Na₂SO₄), concentrated under reducedpressure to give a solid which was used for the next step withoutfurther purification.

1) 6,7,8,9-Tetrahydro-pyrido[2,1-b]quinazolin-11-one

Light orange crystals (41%)

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.83 min. m/z=201 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.00 (4H, m), 3.1 (2H, t), 4.1 (2H, t), 7.5(1H, t), 7.6-7.8 (2H, m), 8.3 (1H, d).

2) 3-fluoro-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Yellow crystals (44%)

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.34 min. m/z=219 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.00 (4H, m), 3.0 (2H, t), 4.1 (2H, t), 7.1(1H, m), 7.2 (1H, d), 8.3 (1H, t).

3) 2-fluoro-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Yellow solid (56%)

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.39 min. m/z=219 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.00 (4H, m), 3.0 (2H, t), 4.1 (2H, t), 7.4(1H, m), 7.6 (1H, m), 7.9 (1H, dd).

4) 2,3-Difluoro-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Yellow crystals (45%)

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.82 min. m/z=237 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.00 (4H, m), 2.95 (2H, t), 4.1 (2H, t), 7.35(1H, q), 8.0 (1H, t).

E. 6-Bromo-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one derivatives

These compounds have been prepared as described for the3-bromo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one derivatives.

1) 6-Bromo-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Pale yellow crystals (55%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.86 min. m/z=280 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.1-2.6 (4H, m), 4.00 (1H, m), 4.4 (1H, m),5.4 (1H, s), 7.5. (1H, t), 7.7 (2H, m), 8.3 (1H, d).

2) 6-Bromo-3-fluoro-6,7,8,9-Tetrahydro-pyrido[2,1-b]quinazolin-11-one

Pale yellow crystals (65%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.21 min. m/z=298 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.1-2.6 (4H, m), 4.00 (1H, m), 4.4 (1H, m),5.4 (1H, s), 7.2-7.5 (2H, m), 8.3 (1H, d).

3) 6-Bromo-2-fluoro-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

White solid (69%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.20 min. m/z=298 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.1-2.6 (4H, m), 4.00 (1H, m), 4.4 (1H, m),5.35 (1H, s), 7.5 (1H, m), 7.7 (1H, m), 7.9 (1H, dd).

4)6-Bromo-2,3-difluoro-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

White solid (55%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.49 min. m/z=316 (M+1).

¹H-NMR (300 MHz; CDCl₃) δ 2.1-2.6 (4H, m), 3.95 (1H, m), 4.4 (1H, m),5.35 (1H, s), 7.45 (1H, t), 8.05 (1H, t).

F.6-(1-Phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-onederivatives

These compounds have been prepared as decribed for the3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-onederivatives (mixture of diastereoisomers).

1)6-(1-Phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Pale yellow solid (72%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.98 and 3.19 min. m/z=320 (M+1).

2)3-Fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Yellow solid (40%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.18 min. m/z=338 (M+1).

3)2-Fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Yellow solid (26%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.14 min. m/z=338 (M+1).

4)2,3-Difluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one

Yellow solid (40%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.15 min. m/z=356 (M+1).

EXAMPLE 11-(9-Oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

To a solution of3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(50 mg, 0.163 mmol) in dry CH₂Cl₂ (1 mL), was added 2-n-propylphenylisocyanate (26.3 mg, 0.163 mmol). The resulting reaction mixture wasstirred at rt under nitrogen for 20 h. The reaction mixture was thenconcentrated under reduced pressure and the residue was purified by FC(AcOEt/heptane: 7/3) to give the title compound as a white foam (45%).LC-MS (MeCN/H₂O: 1/1): R_(t)=3.00 min. m/z=467 (M+1).

EXAMPLE 23-Biphenyl-2-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using with 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(63%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.89 and 5.49 min. m/z=500 (M).

EXAMPLE 33-(2-Ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(55%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.60 and 5.23 min. m/z=468 (M).

EXAMPLE 43-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(62%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.76 and 5.33 min. m/z=470 (M).

EXAMPLE 53-Biphenyl-2-yl-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenylisocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(82%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.01 and 5.61 min. m/z=518 (M).

EXAMPLE 61-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige powder(61%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.06 and 5.61 min. m/z=484 (M).

EXAMPLE 71-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white solid(72%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.92 and 5.61 min. m/z=526 (M).

EXAMPLE 81-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-isopropylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(70%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.98 and 5.48 min. m/z=484 (M).

EXAMPLE 91-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 1-naphthyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a brown oil(77%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.72 and 5.28 min. m/z=492 (M).

EXAMPLE 101-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as an orange oil(75%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.99 and 5.53 min. m/z=484 (M).

EXAMPLE 111-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1using7-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a brown oil(83%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.85 and 5.52 min. m/z=526 (M+1).

EXAMPLE 123-Biphenyl-2-yl-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenylisocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow brownoil (70%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.02 and 5.59 min. m/z=518 (M).

EXAMPLE 133-(2-Ethyl-phenyl)-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-fluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(70%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.77 and 5.32 min. m/z=470 (M).

EXAMPLE 143-Biphenyl-2-yl-1-(6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6,7-difluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenylisocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a pale grey foam(56%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.27 and 5.84 min. m/z=536 (M).

EXAMPLE 151-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6,7-difluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a brown foam(61%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.07 and 5.74 min. m/z=544 (M).

EXAMPLE 161-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6,7-difluoro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a brown foam(67%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.22 and 5.74 min. m/z=502 (M).

EXAMPLE 171-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a pale beige foam(66%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.09 and 5.73 min. m/z=487 (M).

EXAMPLE 181-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 1-naphthyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige solid(47%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.99 and 5.61 min. m/z=509 (M).

EXAMPLE 191-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-isopropylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a grey solid(87%).

LC-MS (MeCN/H₂O: 1/1): R_(t)5.30 and 5.81 min. m/z=501 (M).

EXAMPLE 201-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-]H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(58%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.34 and 5.92 min. m/z=501(M).

EXAMPLE 211-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a pale brown foam(74%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.18 and 5.92 min. m/z=542 (M).

EXAMPLE 223-Biphenyl-2-yl-1-(7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using7-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(72%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.36 and 5.99 min. m/z=535 (M).

EXAMPLE 233-Biphenyl-2-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow oil(22%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.99 and 5.80 min. m/z=515 (M+1).

EXAMPLE 241-(11-Oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(53%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.18 and 5.86 min. m/z=481 (M+1).

EXAMPLE 253-(2-Ethyl-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow oil(72%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.87 and 5.54 min. m/z=467 (M+1).

EXAMPLE 263-(2-Ethoxy-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige solid(41%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.81 and 5.67 min. m/z=483 (M+1).

EXAMPLE 273-Naphthalen-1-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 1-naphthyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige solid(28%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.87 and 5.51 min. m/z=489 (M+1).

EXAMPLE 281-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2,3-difluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(80%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=6.13 min. m/z=517 (M+1).

EXAMPLE 293-Biphenyl-2-yl-1-(2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea (mixture of diatereoisomers)

In analogy to Example 1 using2,3-difluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(48%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.57and 6.22 min. m/z=551 (M+1).

EXAMPLE 301-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2,3-difluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(97%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.35 and 5.92 min. m/z=503 (M+1).

EXAMPLE 311-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethoxy-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2,3-difluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(60%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.22 and 6.07 min. m/z=519 (M+1).

EXAMPLE 323-Biphenyl-2-yl-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using3-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(42%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.38 and 6.10 min. m/z=533 (M+1).

EXAMPLE 331-(3-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using3-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(98%). LC-MS (MeCN/H₂O: 1/1): R_(t)=5.29 and 5.96 min. m/z=499 (M+1).

EXAMPLE 343-(2-Ethoxy-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using3-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a foam (88%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.03 and 5.93 min. m/z=501 (M+1).

EXAMPLE 353-(2-Ethyl-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using3-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a foam (47%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.07 and 5.74 min. m/z=485 (M+1).

EXAMPLE 363-Biphenyl-2-yl-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one (1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow powder(43%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.38 and 6.07 min. m/z=533 (M+1).

EXAMPLE 371-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-1-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as an orange-brownpowder (53%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.29 and 5.94 min. m/z=499 (M+1).

EXAMPLE 383-(2-Ethoxy-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow powder(44%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.03 and 5.86 min. m/z=501 (M+1).

EXAMPLE 393-(2-Ethyl-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenylethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using2-fluoro-6-(1-phenyl-ethylamino)-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazolin-11-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow powder(54%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.07 and 5.72 min. m/z=485 (M+1).

EXAMPLE 401-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using8-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a white foam(74%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.97 and 5.74 min. m/z=542 (M).

EXAMPLE 413-Biphenyl-2-yl-1-(8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using8-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenylisocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a yellow foam(70%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.16 and 5.80 min. m/z=535 (M).

EXAMPLE 421-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using8-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-isopropylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(70%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.11 and 5.67 min. m/z=501 (M).

EXAMPLE 431-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using8-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 1-naphthyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(57%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.83 and 5.46 min. m/z=509 (M).

EXAMPLE 441-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using8-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(64%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.11 and 5.74 min. m/z=501 (M).

EXAMPLE 451-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea(mixture of diatereoisomers)

In analogy to Example 1 using8-chloro-3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a pale beige foam(83%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.86 and 5.53 min. m/z=486 (M).

EXAMPLE 461-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea

In analogy to Example 1 using5-fluoro-3-((S)1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a pale beige foam(57%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.27 and 5.74 min. m/z=485 (M+1).

EXAMPLE 473-Biphenyl-2-yl-1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea

In analogy to Example 1 using5-fluoro-3-((S)1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a green foam(73%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.39 and 5.94 min. m/z=519 (M+1).

EXAMPLE 481-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea

In analogy to Example 1 using5-fluoro-3-((S)1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a pale greensolid (62%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.13 and 5.72 min. m/z=527 (M+1).

EXAMPLE 491-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea

In analogy to Example 1 using3-((S)-1-Phenyl-ethylamino)-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-trifluoromethoxyphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(68%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.39 and 6.14 min. m/z=577 (M+1).

EXAMPLE 501-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea

In analogy to Example 1 using3-((S)-1-Phenyl-ethylamino)-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-n-propylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(54%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.54 and 6.13 min. m/z=535 (M+1).

EXAMPLE 513-(2-Ethyl-phenyl)-l-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea

In analogy to Example 1 using3-((S)-1-Phenyl-ethylamino)-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1eq) and 2-ethylphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(62%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.34 and 5.96 min. m/z=521 (M+1).

EXAMPLE 523-Biphenyl-1-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea

In analogy to Example 1 using3-((S)-1-Phenyl-ethylamino)-8-trifluoromethyl-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one(1 eq) and 2-biphenyl isocyanate (1 eq).

FC (AcOEt/heptane: 7/3) afforded the title compound as a beige foam(72%).

LC-MS (MeCN/H₂O: 1/1): R_(t)=5.64 and 6.22 min. m/z=569 (M+1).

1. Compounds of the general formula (I)

wherein: X is 0 or S; n is the integer 1, 2, or 3; m is the integer 0,1, 2, 3; R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy,aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R⁸CO—, NR⁹R¹⁰CO—,R⁹R¹⁰N—, R⁸OOC—, R⁸SO₂NH—, R¹¹—CO—NH— or R² and R³ together or R¹ and R²together or R³ and R⁴ together may form with the phenyl ring a five, sixor seven-membered ring containing one or two oxygen atoms which areseparated by at least one carbon atom; R⁵ represents aryl, aralkyl,lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl orheterocyclyl-lower alkyl; R⁶ represents hydrogen, lower alkyl,trifluoromethyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—O-lower alkyl,—(CH₂)_(m)—CO₂H, —(CH₂)_(m)—CO₂-lower alkyl, —(CH₂)_(m)CONH₂,—(CH₂)_(m)—CONH-lower alkyl, or —(CH₂)_(m)—CON-(lower alkyl)₂, or—(CH₂)_(m)—N-(lower alkyl)₂; R⁷ represents aryl, aralkyl, lower alkyl,lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, heterocyclyl orheterocyclyl-lower alkyl; R⁸ represents lower alkyl, aryl, aralkyl,heterocyclyl or heterocyclyl-lower alkyl; R⁹and R¹⁰ independentlyrepresent hydrogen, alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl,aralkyl, heterocyclyl or heterocyclyl-lower alkyl; R¹¹ represents loweralkyl, aryl, cycloalkyl, heterocyclyl, R⁹R¹⁰N— or R⁸O—; and opticallypure enantiomers, mixtures of enantiomers, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates, mixture of diastereoisomeric racemates, or meso forms andpharmaceutically acceptable salts thereof.
 2. Compounds of the generalformula I according to claim 1, wherein n is integer 1 or 2, m isinteger 0, 1 or 2, and X represents oxygen.
 3. Compounds of the generalformula I according to claim 1, wherein n is integer 1 or 2, m isinteger 0, R⁵ represents methyl, R⁶ represents phenyl, and X representsoxygen.
 4. A compound according to claim 1, selected from the groupconsisting of1-(9-Oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;3-Biphenyl-2-yl-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;3-(2-Ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;3-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;3-Naphthalen-1-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;3-(2-Ethyl-phenyl)-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;3-Biphenyl-2-yl-1-(6-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-phenyl-ethyl)-urea;1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-propyl-phenyl)-urea;1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;1-(6-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea;1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;1-(7-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;3-Biphenyl-2-yl-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;3-(2-Ethyl-phenyl)-1-(7-fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;1-(6-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1(1-phenyl-ethyl)-urea;1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;1-(7-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;3-Biphenyl-2-yl-1-(7-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;3-Biphenyl-2-yl-1-(8-chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-isopropyl-phenyl)-1-(1-phenyl-ethyl)-urea;1-(8-Chloro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-naphthalen-1-yl-1-(1-phenyl-ethyl)-urea;3-Biphenyl-2-yl-1-(6,7-difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-urea;1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;1-(6,7-Difluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;3-Biphenyl-2-yl-1-butyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;1-Butyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-n-propyl-phenyl)-urea;1-Benzyl-3-biphenyl-2-yl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;1-Benzyl-3-(2-ethoxy-phenyl)-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-urea;1-Benzyl-1-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-3-(2-n-propyl-phenyl)-urea;3-Biphenyl-2-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;3-(2-Ethyl-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;3-(2-Ethoxy-phenyl)-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;3-Naphthalen-1-yl-1-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;3-Biphenyl-2-yl-1-(2,3-difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethyl-phenyl)-1-(1-phenyl-ethyl)-urea;1-(2,3-Difluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-(2-ethoxy-phenyl)-1-(1-phenyl-ethyl)-urea;3-Biphenyl-2-yl-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;1-(3-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;3-(2-Ethoxy-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;3-(2-Ethyl-phenyl)-1-(3-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;3-(2-Ethyl-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;3-(2-Ethoxy-phenyl)-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;3-Biphenyl-2-yl-1-(2-fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-1-(1-phenyl-ethyl)-urea;1-(2-Fluoro-11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-6-yl)-3-naphthalen-1-yl-1-(1-phenyl-ethyl)-urea;1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;3-Biphenyl-2-yl-1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1((S)-1-phenyl-ethyl)-urea;1-(5-Fluoro-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;1-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-trifluoromethoxy-phenyl)-urea;1-(9-Oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-3-(2-n-propyl-phenyl)-urea;3-(2-Ethyl-phenyl)-1-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea;and3-Biphenyl-l-(9-oxo-8-trifluoromethyl-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)-1-((S)-1-phenyl-ethyl)-urea.5. A pharmaceutical composition comprising one or more compounds of anyone of claims 1 to 4, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier and/or adjuvant.
 6. (Cancelled).7. A method of treating or preventing diseases or disorders where anantagonist of a human orexin receptor is required, which comprisesadministering to a subject in need thereof an effective amount of acompound as claimed in any one of claims 1 to 4, or a pharmaceuticallyacceptable salt thereof.
 8. A process for the manufacture ofpharmaceutical compositions comprising mixing one or more compounds asclaimed in any one of claims 1 to 4, or a pharmaceutically acceptablesalt or salts thereof, as active ingredients with a pharmaceuticallyacceptable excipient and/or adjuvant.
 9. The method of claim 7 furthercomprising administering in combination with the compound other orexinreceptor antagonists, lipid lowering agents, anorectic agents, sleepinducing agents, antidepressants or other drugs beneficial for theprevention or treatment of obesity, sleep disorders, cardiovasculardisorders, cancer, pain, depression, schizophrenia or neurodegenerativedisorders.
 10. A compound as described as end-product in any one ofexamples 1 to
 63. 11. (Cancelled).